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PMID:24732013

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Citation

Wang, YJ, Guo, XL, Li, SA, Zhao, YQ, Liu, ZC, Lee, WH, Xiang, Y and Zhang, Y (2014) Prohibitin is involved in the activated internalization and degradation of protease-activated receptor 1. Biochim. Biophys. Acta 1843:1393-401

Abstract

The protease-activated receptor 1 (PAR1) is a G-protein-coupled receptor that is irreversibly activated by either thrombin or metalloprotease 1. Due this irrevocable activation, activated internalization and degradation are critical for PAR1 signaling termination. Prohibitin (PHB) is an evolutionarily conserved, ubiquitously expressed, pleiotropic protein and belongs to the stomatin/prohibitin/flotillin/HflK/C (SPFH) domain family. In a previous study, we found that PHB localized on the platelet membrane and participated in PAR1-mediated human platelet aggregation, suggesting that PHB likely regulates the signaling of PAR1. Unfortunately, PHB's exact function in PAR1 internalization and degradation is unclear. In the current study, flow cytometry revealed that PHB expressed on the surface of endothelial cells (HUVECs) but not cancer cells (MDA-MB-231). Further confocal microscopy revealed that PHB dynamically associates with PAR1 in a time-dependent manner following induction with PAR1-activated peptide (PAR1-AP), though differently between HUVECs and MDA-MB-231 cells. Depletion of PHB by RNA interference significantly inhibited PAR1 activated internalization and led to sustained Erk1/2 phosphorylation in the HUVECs; however, a similar effect was not observed in MDA-MB-231 cells. For both the endothelial and cancel cells, PHB repressed PAR1 degradation, while knockdown of PHB led to increased PAR1 degradation, and PHB overexpression inhibited PAR1 degradation. These results suggest that persistent PAR1 signaling due to the absence of membrane PHB and decreased PAR1 degradation caused by the upregulation of intracellular PHB in cancer cells (such as MDA-MB-231 cells) may render cells highly invasive. As such, PHB may be a novel target in future anti-cancer therapeutics, or in more refined cancer malignancy diagnostics.

Links

PubMed Online version:10.1016/j.bbamcr.2014.04.005

Keywords

Cell Line, Tumor; Cell Movement/drug effects; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells/cytology; Human Umbilical Vein Endothelial Cells/metabolism; Humans; Microscopy, Confocal; Mitogen-Activated Protein Kinase 1/genetics; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/genetics; Mitogen-Activated Protein Kinase 3/metabolism; Organ Specificity; Peptides/pharmacology; Protein Transport/drug effects; Proteolysis/drug effects; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Receptor, PAR-1/antagonists & inhibitors; Receptor, PAR-1/genetics; Receptor, PAR-1/metabolism; Repressor Proteins/antagonists & inhibitors; Repressor Proteins/genetics; Repressor Proteins/metabolism; Signal Transduction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PAR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35232

F

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PAR1

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PAR1

located_in

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PAR1

located_in

GO:0005770: late endosome

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PHB

enables

GO:0031871: proteinase activated receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P25116

F

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PHB

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PHB

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PHB

located_in

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PHB

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PHB

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PHB

involved_in

GO:0070373: negative regulation of ERK1 and ERK2 cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PHB

involved_in

GO:0045745: positive regulation of G protein-coupled receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PHB

involved_in

GO:0042177: negative regulation of protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P25116)

Seeded From UniProt

complete

HUMAN:PAR1

part_of

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PAR1

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002618)

Seeded From UniProt

complete

HUMAN:PAR1

part_of

GO:0005770: late endosome

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002618)

Seeded From UniProt

complete

Notes

See also

References

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